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The biochemical variations induced in human primary hepatocyte cultures by reference activators of xenoreceptor CAR (NR1I3) and PXR (NR1I2), i.e., rifampicin, phenobarbital, and 6-(4-chlorophenyl)imidazo[2,1-b] [1,3]thiazole-5-carbaldehyde O-3,4-dichlorobenzyl) oxime (CITCO), were investigated using a global metabonomics approach. Cultured human hepatocytes were treated with the three drugs before analysis of intracellular and extracellular media by ultra performance liquid chromatography/time-of-flight-mass spectrometry (UPLC/TOF-MS) technique, in order to list endogenous compounds potentially related to a PXR or CAR induction mechanism and to identify drug metabolites related to each treatment. The emphasis was put on the quality of the analytical data (dilution/filtration strategy before data processing) and on the appropriate pattern recognition techniques. In cellular media, the most significant variations seen in the data are not related to the treatments but to the source of hepatocytes, illustrating the importance of the genetic and/or environmental background in human liver experiments. However when applying classical multivariate statistical approaches (principal component analysis (PCA) and orthogonal partial least squares (O-PLS)), the statistical weight due to drug metabolites, present only in the treated groups, hinders the interpretation because of their predominance compared to most of the changes seen in endogenous metabolites. A new statistical approach, called shared and unique structure (SUS) plot, enabling the comparison of different treatments having the same control has been applied, allowing separation of clearly exogenous variables (drug metabolites) from endogenous biomarkers. Endogenous variables (either up- or down-regulated) have been attributed specifically to the impact of rifampicin (PXR ligand), CITCO (CAR ligand), and phenobarbital (CAR and PXR activator) on the biological regulation pathways of the hepatocytes. This global approach coupled to a statistical pretreatment of the data, enabling the separate capture of both drug related and drug induced biomarkers, represents a powerful technique for future mechanistic studies using cellular tools.

Background: The aim of this meta-analysis was to explore the magnitude of the association between pharmacokinetics of adalimumab and clinical response in patients with inflammatory bowel disease., Methods: A literature search was performed up to December 2013. MEDLINE, EMBASE, Cochrane, and meeting abstracts were reviewed. Studies were included if they analyzed the association of trough levels of adalimumab (TRA) or antibodies against adalimumab (AAA) with clinical response in adult or pediatric inflammatory bowel disease. A Mantel-Haenszel pooled risk estimate provided a measure of the association., Results: Fourteen studies enrolling 1941 patients with inflammatory bowel disease were included in the systematic review. Thirteen studies analyzed clinical outcomes according to TRA. In only 1 study, there was no correlation between high TRA and clinical response. Six of the 7 studies reported a negative correlation between AAA and clinical outcomes. Six studies enrolling 536 patients (Crohn's disease [CD] only) met the meta-analysis inclusion criteria. The pooled odds ratio (OR) for loss of clinical response to adalimumab in patients with CD (N = 4) with positive AAAs was 10.15 (95% confidence interval [CI]: 3.90-26.40, P < 0.0001). Patients with CD with TRA over a predefined cutoff were more likely to be in clinical remission with an OR of 2.6 (95% CI: 1.79-3.77, P < 0.0001). The association was stronger if the analysis was limited to the adult population (N = 3, OR: 7.05, 95% CI: 3.58-13.9, P < 0.0001)., Conclusions: The presence of AAA is associated with a higher risk of loss of clinical response to adalimumab, whereas high TRA is associated with greater clinical response rates in CD. More data are needed in ulcerative colitis.

Background: A previous meta-analysis suggested that 6-thioguanine nucleotides levels are associated with clinical remission in inflammatory bowel disease. It was criticized because of the relatively small number of patients included in this meta-analysis and heterogeneity between studies. Recent studies provided conflicting results, and the source of those discrepancies has yet to be explored., Methods: A comprehensive, computerized literature search was conducted in Medline, ISI Web of Science, and EMBASE until December 31, 2012. A combined odd ratio with its 95% confidence interval was calculated using a fixed effects model based on the Mantel-Haenszel method. Between-study heterogeneity was assessed using Cochran's Q statistic., Results: Seventeen studies enrolling 2049 patients with inflammatory bowel disease were analyzed. A significant heterogeneity was found in the overall analysis (P = 0.005). As heterogeneity among studies could be explained by differences in metabolite assay methods, an analysis including only studies using the reference method by Lennard et al (N = 10) was performed, and the pooled odds ratio for clinical remission among patients with 6-thioguanine nucleotides levels over a cut-off value between 230 and 260 pmol/8.10^8 RBC was 3.15 (95% confidence interval, 2.41-4.11)., Conclusions: This meta-analysis clearly establishes an association between 6-thioguanine nucleotides levels and clinical remission rates in patients with inflammatory bowel disease and explains the heterogeneity of results among selected studies. The lack of standardization in 6-thioguanine nucleotides assays is responsible for recent contradictory results. Whether therapeutic drug monitoring of thiopurines should be systematically used in clinical practice in inflammatory bowel disease to improve disease outcomes will require further investigation.

Background: Data on the value of therapeutic drug monitoring of infliximab (IFX) to predict mucosal healing (MH) in inflammatory bowel diseases (IBD) are scarce., Methods: All consecutive patients with IBD receiving ongoing IFX (5 mg/kg) treatment and developing secondary failure to IFX were enrolled in a prospective study between June 2010 and May 2011. IFX trough levels, antibodies to IFX concentrations, C-reactive protein levels, and fecal calprotectin were measured before IFX optimization and at week 8. A proctosigmoidoscopy was performed on the day of first IFX optimization and at week 8 in all patients with ulcerative colitis (UC). MH was defined by fecal calprotectin <250 μg/g stools in Crohn's disease (CD) and by an endoscopic Mayo score of 0 or 1 in UC., Results: This study included 52 patients with IBD: 34 patients with CD (mean Crohn's Disease Activity Index, 300; mean C-reactive protein, 28 ± 10 mg/L; mean fecal calprotectin, 705 ± 300 μg/g) and 18 patients with UC (mean Simple Clinical Colitis Activity Index, 7; mean Mayo endoscopic score, 3). After IFX dose intensification, half of CD and UC patients achieved MH. Increase in IFX trough levels (called "delta IFX" in micrograms per milliliter) was associated with MH in both CD and UC (P = 0.001). A delta IFX >0.5 μg/mL was associated with MH (sensitivity [se], 0.88; specificity [sp], 0.77; P = 0.0001, area under the receiver operating characteristic curve, 0.89). On multivariate analysis, the only factor associated with MH after IFX optimization was a delta IFX >0.5 µg/mL (likelihood ratio = 2.02; 95% confidence interval, 1.01-4.08; P = 0.048) in patients with IBD., Conclusions: Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.